Perm1 is a Novel Regulator of Cardiac Energetics and Function

Perm1 是一种新型的心脏能量和功能调节剂

• 批准号: 10631449
• 负责人: Stavros George Drakos
• 金额: $ 0.53万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-20 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10631449
• 关键词: Ablation; Adult; Anabolism; Animal Genetics; Animal Model; Bioenergetics; Biogenesis; Biological Assay; Cardiac; Cardiac Myocytes; Cell Nucleus; Cells; Citric Acid Cycle; Complex; Congestive Heart Failure; Crista ampullaris; Data; Defect; Development; Down-Regulation; EFRAC; ERR1 protein; Epigenetic Process; Exercise; Exhibits; Fatigue; Feedback; Functional disorder; Gene Delivery; Gene Expression; Genes; Genetic Models; Genetic Transcription; Global Change; Heart; Heart Diseases; Heart failure; Human; Impairment; Knock-out; Knowledge; Link; Luciferases; Maintenance; Metabolic; Mitochondria; Mitochondrial Myopathies; Mus; Muscle; Muscular Atrophy; Myocardial; Myocardial dysfunction; Oxidative Phosphorylation; PPAR gamma; Pathologic; Pathway interactions; Patients; Phenotype; Physiological; Production; Proteins; Recovery; Regulation; Regulatory Pathway; Reporter Genes; Resistance; Respiration; Response Elements; Role; Signal Pathway; Skeletal Muscle; Stimulus; Stress Tests; System; Testing; Time; Transcription Coactivator; Work; base; chromatin immunoprecipitation; cofactor; density; energy balance; functional adaptation; heart function; heart metabolism; histone methyltransferase; induced pluripotent stem cell derived cardiomyocytes; interdisciplinary approach; knock-down; novel; novel therapeutic intervention; peer; postnatal development; pressure; promoter; response; skeletal; therapeutic target; transcription factor

PROJECT SUMMARY Energy metabolic reprogramming occurs in the developing and diseased hearts. Mitochondria are responsible for coordinating cellular energy production in response to physiological and pathological stimuli. The mitochondrial regulatory system is highly regulated by several transcription factors and coactivators that orchestrate the expression of genes involved in mitochondrial biogenesis, maintenance, and respiration capacity. However, the transcriptional regulatory machinery in mitochondrial bioenergetics is complex, and it is still not completely understood how mitochondria coordinately respond to physiological and pathological stimuli. Perm1 (“PGC-1 and ERR regulator in muscle 1”) was recently identified in skeletal muscle, as a novel muscle-specific protein that regulates mitochondrial oxidative capacity. Perm1 is induced by exercise, and the increased expression of Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in mouse skeletal muscle. These findings point to a new path towards understanding mitochondrial myopathies and muscle atrophies. However, the role of Perm1 in the heart has never been investigated. Moreover, the regulatory mechanism of Perm1 in mitochondrial function is currently unknown. Our preliminary data suggest the significant role of Perm1 in cardiac pathophysiology: (1) Perm1 is highly expressed in the heart and is downregulated in the mouse failing heart and in patients with heart failure; (2) Perm1 expression is increased during differentiation and maturation in human iPS cell-derived cardiomyocytes; (3) Perm1 knockdown in cultured cardiomyocytes leads to reduced mitochondrial respiration capacity. Furthermore, our preliminary data suggest that Perm1 controls mitochondrial function through the regulation of ERRα, a well-known transcription factor that orchestrates the expression of genes in mitochondrial bioenergetics. This application will leverage a genetic animal model and state-of-the art multisystems approach to conceptually advance our understanding of mitochondrial bioenergetics in the heart. Specifically, this work is expected to demonstrate that Perm1 is a critical regulator of mitochondrial biosynthesis and energetics in the heart through the ERRα pathway. Furthermore, this study will determine if gene delivery of Perm1 to the heart protects against mitochondrial impairment and cardiac dysfunction in the setting of pressure-overload-induced heart failure. Conclusive evidence that Perm1 is a novel transcriptional cofactor of the mitochondrial regulatory pathway in the heart will profoundly advance our knowledge of cardiac metabolism, and may suggest new therapeutic approaches for heart failure.

项目总结 能量代谢重新编程发生在发育中和患病的心脏中。线粒体是 负责协调细胞能量生产，以应对生理和病理 刺激物。线粒体调节系统受几种转录因子和 协调线粒体生物发生、维持、 和呼吸量。然而，线粒体中的转录调控机制 生物能量学是复杂的，目前还不完全了解线粒体如何协调反应 对生理和病理刺激。 Perm1(“肌肉中的PGC-1和ERR调节器1”)最近在骨骼肌中被鉴定为一种 调节线粒体氧化能力的新型肌肉特异性蛋白。Perm1由以下因素诱导 运动，Perm1表达的增加增强了线粒体的生物发生，氧化能力， 以及小鼠骨骼肌的疲劳性。这些发现指出了一条新的道路， 了解线粒体肌病和肌肉萎缩。然而，Perm1在心脏中的作用 从未被调查过。此外，Perm1对线粒体功能的调节机制是 目前尚不清楚。我们的初步数据提示Perm1在心脏疾病中的重要作用 病理生理学：(1)Perm1在心脏中高表达，在衰竭小鼠中表达下调 (2)Perm1在分化和分化过程中表达增加； 人iPS细胞来源的心肌细胞的成熟；(3)培养心肌细胞中Perm1基因的下调 导致线粒体呼吸能力降低。此外，我们的初步数据表明， Perm1通过调节转录因子ERRα来控制线粒体功能 这就协调了线粒体生物能量学中的基因表达。 该应用程序将利用遗传动物模型和最先进的多系统方法 从概念上推进我们对心脏线粒体生物能量学的理解。具体地说，这 预计工作将证明Perm1是线粒体生物合成的关键调节因子，并 心脏中的能量通过ERRα途径。此外，这项研究将确定基因是否 Perm1心脏给药对心肌线粒体损伤和心功能不全的保护作用 压力超负荷所致心力衰竭的设定。Perm1是一部小说的确凿证据 心脏中线粒体调节途径的转录辅助因子将深刻地促进我们的 心脏新陈代谢知识，并可能建议新的治疗心力衰竭的方法。